CHAPTER 1

INTRODUCTION

Herpes zoster (shingles) is an acute, cutaneous viral infection caused by the reactivation
of varicella-zoster virus (VZV), a herpesvirus that is the cause of varicella (chickenpox).
Differences in clinical manifestations between varicella and herpes zoster apparently depend on
an individual's immune status; those with no previous exposure to VZV, most commonly
children, develop the clinical syndrome of varicella, whereas those with circulating varicella
antibodies develop a localized recrudescence, zoster.

Zoster probably results most often from a failure of the immune system to contain latent
VZV replication. Whether other factors, such as radiation, physical trauma, certain medications,
other infections, and stress, also can trigger zoster has not been determined with certainty. Nor is
it entirely clear why circulating varicella antibodies and cell-mediated immune mechanisms do
not prevent recurrent overt disease, as is common with most other viral illnesses.

The incidence of zoster appears to be inversely correlated with the host’s capacity to
mount a cellular immune response. However, many patients with zoster apparently have normal
immunity. In these patients, zoster is postulated to occur when VZV antibody titers and cellular
immunity drop to levels that no longer are completely effective in preventing viral invasion.
Evidence for this hypothesis includes the observation that pediatricians, who presumably are
routinely reexposed to VZV and thus maintain high levels of immunity, seldom develop zoster.

Herpes zoster manifests in many ways. It should not be considered simply a self-limited
dermatomal rash with pain. VZV infection is an acute neurologic disease that warrants
immediate evaluation. That VZV is always a benign disorder is a common misperception. Once
VZV infection resolves, many individuals continue to suffer pain—a condition known as
postherpetic neuralgia (PHN). 1
 CHAPTER II
LITERATURE REVIEW

Definition

Herpes zoster (shingles) is an acute, cutaneous viral infection caused by the reactivation

of varicella-zoster virus (VZV), a herpesvirus that is the cause of varicella (chickenpox).

Differences in clinical manifestations between varicella and herpes zoster apparently depend on

an individual's immune status; those with no previous exposure to VZV, most commonly

children, develop the clinical syndrome of varicella, whereas those with circulating varicella

antibodies develop a localized recrudescence, zoster. 2

Epidemiology

In the United States, approximately 95% of adults—and 99.5% of adults aged 40 years or
older—have antibodies to VZV and thus are vulnerable to reactivation of infection.[38] A person
of any age with a previous varicella infection may develop zoster, but the incidence increases
with advancing age as a consequence of declining immunity.

Approximately 4% of patients with herpes zoster will develop a recurrent episode later in
life.[39] Recurrent zoster occurs almost exclusively in people who are immunosuppressed.
Approximately 25% of patients with HIV and 7-9% of those receiving renal transplantation or
cardiac transplantation experience a bout of zoster.

HZO represents 10-15% of all cases of HZ. Approximately half of these patients develop
complications of HZO. The risk of ophthalmic complications in patients with herpes zoster does
not seem to correlate with age, sex, or severity of the rash.

Before the advent of widespread vaccination, an estimated 4 million cases of primary

VZV infection occurred annually in the United States alone.Infection was nearly universal by the
end of the teenage years, with studies showing only 10% of persons older than age 15 years as
remaining susceptible to infection.

Over the period of a lifetime, 10-20% of those with primary infections went on to
experience episodes of herpes zoster. High-risk groups, such as elderly populations and
immunocompromised people, might experience cumulative incidences as high as 50% . The
estimated annual number of herpes zoster cases in the United States is approximately 1 million.

Since the introduction of widespread vaccination for varicella in 1995, the incidence of
primary VZV infection in the United States has been reduced by up to 90%. However, the effect
of this vaccination, as well as that of the subsequently approved vaccination for herpes zoster, on
the current and future incidence of herpes zoster remains to be determined.3

Etiology

Herpes zoster is caused by VZV infection. VZV is an enveloped, double-stranded DNA

virus belonging to the Herpesviridae family; its genome encodes approximately 70 proteins. In
humans, primary infection with VZV occurs when the virus comes into contact with the mucosa
of the respiratory tract or conjunctiva. From these sites, it is distributed throughout the body.
After primary infection, the virus migrates along sensory nerve fibers to the satellite cells of
dorsal root ganglia where it becomes dormant.

Reactivation of VZV that has remained dormant within dorsal root ganglia, often for decades
after the patient’s initial exposure to the virus in the form of varicella (chickenpox), results in
herpes zoster. Exactly what triggers this reactivation has not yet been determined precisely, but
likely candidates (alone, or in combination) include the following:

 External reexposure to the virus

 Acute or chronic disease processes (particularly malignancies and infections)
 Medications of various types
 Emotional stress
 The reason why one dorsal root ganglion experiences reactivation of its stored viral load
preferentially over another ganglia is unclear. Diminished cellular immunity seems to increase
the risk of reactivation, in that the incidence increases with age and in immunocompromised
persons.

Zoster can be a presenting symptom of hyperparathyroidism, and it occurs twice as often

(frequency, 3.7%) among patients with hypercalcemia as it does among age-matched cohorts of
patients older than 40 years who have normal calcium levels.

Patofisiology

VZV infection gives rise to 2 distinct syndromes. The primary infection, chickenpox, is a
contagious and usually benign febrile illness. After this infection resolves, viral particles remain
in the dorsal root or other sensory ganglia, where they may lay dormant for years to decades.

In this latent period, host immunologic mechanisms suppress replication of the virus, but
VZV reactivates when the host mechanisms fail to contain the virus. Such failure may result
from a wide spectrum of conditions, ranging from stress to severe immunosuppression;
occasionally, it follows direct trauma. VZV viremia occurs frequently with chickenpox but also
may arise with herpes zoster, albeit with a lower viral load.

Once VZV is activated at the spinal root or cranial nerve neurons, an inflammatory response
occurs that also encompasses the leptomeninges; both plasma cells and lymphocytes are noted.
This inflammation in the dorsal root ganglion can be accompanied by hemorrhagic necrosis of
nerve cells. The result is neuronal loss and fibrosis.

The frequency of dermatologic involvement is correlated with the centripetal distribution

of the initial varicella lesions. This pattern suggests that the latency may arise from contiguous
spread of the virus during varicella from infected skin cells to sensory nerve endings, with
subsequent ascent to the ganglia. Alternatively, the ganglia may become infected
hematogenously during the viremic phase of varicella, and the frequency of the dermatome
involvement in herpes zoster may reflect the ganglia most often exposed to reactivating stimuli.
 The appearance of the cutaneous rash due to herpes zoster coincides with a profound
VZV-specific T-cell proliferation. Production of interferon alfa appears with the resolution of
herpes zoster. In immunocompetent patients, specific antibodies (immunoglobulins G, M, and A
[IgG, IgM, and IgA]) appear more rapidly and reach higher titers during reactivation (herpes
zoster) than during the primary infection. The patient has a long-lasting, enhanced, cell-mediated
immunity response to VZV.

The anatomic location of the involved dermatome often determines the specific
manifestations. When cervical and lumbar roots are involved, motor involvement, which is often
overlooked, may be evident, depending on the virulence or extent of migration. In at least 1 case
of motor neuron involvement, lymphocytic infiltration and myelin breakdown were observed
with preservation of axons.

Herpes zoster infections are contagious to persons with no previous immunity to VZV.
However, herpes zoster is estimated to be only one third as contagious as primary varicella. It is
transmitted either via direct contact with the lesions or via the respiratory route.

Clinical Manifestation

The clinical manifestations of herpes zoster can be divided into the following 3 phases:

 Preeruptive phase (preherpetic neuralgia)

 Acute eruptive phase
 Chronic phase (PHN)

The preeruptive phase is characterized by the following:

 Sensory phenomena along 1 or more skin dermatomes, lasting 1-10 days (average, 48
hours)
 Phenomena usually are noted as pain or, less commonly, itching or paresthesias[3]
 Pain may simulate headache, iritis, pleurisy, brachial neuritis, cardiac pain, appendicitis
or other intra-abdominal disease, or sciatica
  Other symptoms, such as malaise, myalgia, headache, photophobia, and, uncommonly,
fever

The acute eruptive phase is marked by the following:

 Patchy erythema, occasionally accompanied by induration, in the dermatomal area of

involvement
 Regional lymphadenopathy, either at this stage or subsequently
 Grouped herpetiform vesicles developing on the erythematous base (the classic finding)
 Cutaneous findings that typically appear unilaterally, stopping abruptly at the midline of
the limit of sensory coverage of the involved dermatome
 Vesicular involution: Vesicles initially are clear but eventually cloud, rupture, crust, and
involute
 After vesicular involution, slow resolution of the remaining erythematous plaques,
typically without visible sequelae
 Scarring can occur if deeper epidermal and dermal layers have been compromised by
excoriation, secondary infection, or other complications
 Almost all adults experience pain, typically severe
 A few experience severe pain without a vesicular eruption (ie, zoster sine herpete)
 Symptoms tend to resolve over 10-15 days
 Complete healing of lesions may require up to a month

Diagnosis

Diagnosis of herpes zoster is based primarily on the history and physical findings. In
most cases, confirming the diagnosis via laboratory testing has no utility. In select patient
populations, however—particularly immunocompromised patients—the presentation of herpes
zoster can be atypical and may require additional testing.

Laboratory studies for VZV include the following:

 Direct fluorescent antibody (DFA) testing of vesicular fluid or a corneal lesion

 Polymerase chain reaction (PCR) testing of vesicular fluid, a corneal lesion, or blood
  Tzanck smear of vesicular fluid (lower sensitivity and specificity than DFA or PCR).

PHN is characterized by the following:

 Persistent or recurring pain lasting 30 or more days after the acute infection or after all
lesions have crusted (9-45% of all cases)
 Pain usually is confined to the area of original dermatomal involvement
 The pain can be severe and incapacitating
 Pain can persist for weeks, months, or years
 Slow resolution of pain is especially common in the elderly
 PHN is observed more frequently after cases of herpes zoster ophthalmicus (HZO) and in
instances of upper-body dermatomal involvement
 Less common postherpetic sequelae include hyperesthesia or, more rarely, hypoesthesia
or anesthesia in the area of involvement

Common features of herpes zoster ophthalmicus are as follows:

 Classic symptoms and lesions of herpes zoster

 Ophthalmic manifestations including conjunctivitis, scleritis, episcleritis, keratitis
iridocyclitis, Argyll-Robertson pupil, glaucoma, retinitis, choroiditis, optic neuritis, optic
atrophy, retrobulbar neuritis, exophthalmos, lid retraction, ptosis, and extraocular muscle
palsies

Management

Episodes of herpes zoster are generally self-limited and resolve without intervention; they tend to
be more benign and mild in children than in adults.

Conservative therapy includes the following:

 Nonsteroidal anti-inflammatory drugs (NSAIDs)

  Wet dressings with 5% aluminum acetate (Burrow solution), applied for 30-60 minutes 4-
6 times daily
 Lotions (eg, calamine)

Primary medications for acute zoster–associated pain include the following:

 Narcotic and nonnarcotic analgesics (both systemic and topical)

 Neuroactive agents (eg, tricyclic antidepressants [TCAs])
 Anticonvulsant agents

Steroid treatment for herpes zoster is traditional but controversial. Typically, a substantial dose
(eg, 40-60 mg of oral prednisone every morning) typically is administered as early as possible in
the course of the disease and is continued for 1 week, followed by a rapid taper over 1-2 weeks.

Antiviral therapy for herpes zoster may decrease the length of time for new vesicle formation,
the number of days to attain complete crusting, and the days of acute discomfort. Usually, the
earlier antiviral medications are started, the more effective they are in shortening the duration of
zoster and in preventing or decreasing the severity of PHN. Ideally, therapy should be initiated
within 72 hours of symptom onset.

Oral treatment with the following has been found beneficial:

 Acyclovir
 Famciclovir
 Valacyclovir

Hospital admission should be considered for patients with any of the following:

 Severe symptoms
 Immunosuppression
 Atypical presentations (eg, myelitis)
 Involvement of more than 2 dermatomes
 Significant facial bacterial superinfection
 Disseminated herpes zoster
  Ophthalmic involvement
 Meningoencephalopathic involvement

Prevention and treatment of postherpetic neuralgia

Prompt treatment of acute zoster and its associated pain (eg, with antiviral therapy) can prevent
the development of PHN. Once PHN has developed, various treatments are available, including
the following:

 Neuroactive agents (eg, TCAs)

 Anticonvulsant agents (eg, gabapentin,pregabalin)
 Narcotic and nonnarcotic analgesics, both systemic (eg, opioids) and topical

A live attenuated VZV vaccine introduced in 2005 (Zostavax) has demonstrated a reduction in
the incidence rate of herpes zoster. It is approved for use in patients 50 years of age and older.